Dietary and genetic probes of atherogenic dyslipidemia

A goal of dietary management of cardiovascular disease risk in patients with obesity and metabolic syndrome is improvement in the atherogenic dyslipidemia comprising elevated triglyceride, reduced high-density lipoprotein (HDL) cholesterol, and increased numbers of small, dense low-density lipoprotein (LDL) particles. Individuals with a genetically influenced trait characterized by a high proportion of small, dense LDL (phenotype B) respond to a low-fat, high-carbohydrate diet with greater reduction of LDL cholesterol, apoprotein B, and mid-sized LDL2 particles than unaffected subjects (phenotype A). In contrast, in phenotype A subjects there is a reciprocal shift from large LDL1 to small LDL3 such that a high proportion convert to phenotype B. There is evidence for heritable effects on these diet-induced subclass changes and for the involvement of specific genes. For example, a haplotype of the APOA5 gene associated with increased plasma triglyceride and small, dense LDL predicts greater diet-induced reduction of LDL2, a haplotype-specific effect that is strongly correlated with both increased VLDL precursors and LDL4 products. Understanding of such diet-genotype interactions may help to elucidate mechanisms that are responsible for phenotype B and for its differential dietary responsiveness. This information may also ultimately help in identifying those individuals who are most likely to achieve cardiovascular risk benefit from specific dietary interventions.     

Erectile dysfunction in healthy subjects predicts reduced coronary flow velocity reserve

Low density lipoproteins (LDL) do not show in humans a normal distribution and comprise two different main fractions: large, buoyant (phenotype pattern A) and small, dense (phenotype pattern B) particles, that differ not only in size and density but also in physicochemical composition, metabolic behaviour and atherogenicity. The prevalence of small, dense LDL changes with age (30-35% in adult men, 5-10% in men <20 years and in pre-menopausal women, 15-25% in postmenopausal women) and is genetically influenced, with a heritability ranging from 35% to 45%. Small, dense LDL correlate negatively with plasma HDL levels and positively with plasma triglyceride levels and are associated with the metabolic syndrome and with increased risk for cardiovascular disease and diabetes mellitus. LDL size seems also to be an important predictor of cardiovascular events and progression of coronary artery disease and the predominance of small dense LDL has been accepted as an emerging cardiovascular risk factor by the National Cholesterol Education Program Adult Treatment Panel III. In addition, patients with acute myocardial infarction show an early reduction of LDL size, which persists during hospitalization and seems to precede all other plasma lipoprotein modifications. However, it is still on debate whether to measure the LDL size routinely and in which categories of patients. Since the therapeutic modulation of small, dense LDL particles is of great benefit in reducing the atherosclerotic risk, the LDL size measurement should be extended to patients at high risk of coronary artery disease as much as possible.     

Small, dense low-density-lipoproteins and the metabolic syndrome

Small, dense low-density-lipoproteins (LDL) are associated with increased risk for cardiovascular diseases and diabetes mellitus and a reduction in LDL size has been reported in patients with coronary and non-coronary forms of atherosclerosis. LDL size has been accepted as an important predictor of cardiovascular events and progression of coronary artery disease as well as an emerging cardiovascular risk factor by the National Cholesterol Education Program Adult Treatment Panel III. Small, dense LDL, with elevated triglyceride levels and low HDL-cholesterol concentrations, constitute the 'atherogenic lipoprotein phenotype (ALP)', a form of atherogenic dyslipidemia that is a feature of type 2 diabetes and the metabolic syndrome. LDL size and subclasses show specific alterations in patients with the metabolic syndrome that probably significantly increase their cardiovascular risk; however, so far it has not been recommended to incorporate LDL size measurements in treatment plans, when hypolipidemic therapies are installed. Patients with type 2 diabetes are at high cardiovascular risk and it is still on debate if the treatment goals may be identical or whether there are distinct groups with different cardiovascular risks and hence with different treatment goals. Measurements beyond traditional lipids, such as measurements on the presence of small, dense LDL in patients with the metabolic syndrome, may help to identify cardiovascular risk subgroups. In addition, it might be possible in the future to individualize hypolipidemic treatments if more than the traditional lipids are taken into account. LDL size measurement may potentially help to assess cardiovascular risk within the metabolic syndrome and adapt the treatment goals thereafter.     

Using inflammatory biomarkers to guide lipid therapy

Inflammation plays a fundamental role in the pathophysiology of atherothrombotic cardiovascular disease, and lipid-lowering agents appear to have clinically relevant anti-inflammatory properties. In addition to low-ering low-density lipoprotein (LDL) cholesterol, statins improve endothelial function, are clinically effective in a time frame that often precedes LDL reduction, and lower inflammatory markers such as C-reactive protein (CRP) in a largely LDL-independent manner for individual patients. Data from the CARE, AFCAPS/TexCAPS, PROVE IT-TIMI 22, REVERSAL, and A to Z trials suggest that statins provide greater clinical benefit in those who achieve LDL and CRP reductions than in those who achieve LDL reduction alone. We discuss evidence underlying potential anti-inflammatory properties of several lipid-lowering therapies, their impact on measures of endothelial function and vascular inflammation and on subsequent risk reduction, and the use of inflammatory biomarkers as an adjunct to LDL in the monitoring of lipid-lowering therapy.     

The significance of low-density-lipoproteins size in vascular diseases.

Low density lipoproteins (LDL) comprise in humans two different main fractions: large, buoyant and small, dense particles. Small, dense LDL particles correlate negatively with plasma HDL levels and positively with plasma triglyceride concentrations and are associated with the metabolic syndrome and increased risk for cardiovascular disease. LDL size seems to be an important predictor of cardiovascular events and progression of coronary heart disease (CHD). In addition, several studies have suggested that therapeutic modulation of specific LDL subclasses may be of great benefit in reducing the atherosclerotic risk. Therefore, LDL size measurement may be of potential value in the clinical assessment and management of patients at high risk of CHD, a category that comprises individuals with non-coronary forms of atherosclerosis: peripheral arterial disease, carotid artery disease, abdominal aortic aneurysm. Potentially, screening for the presence of small, dense LDL in patients with those clinical forms of atherosclerosis may identify those with even higher vascular risk and may contribute in directing specific anti-atherosclerotic treatments in order to prevent new vascular events in the same or another district. However, to-date, not so many studies have investigated the LDL size in patients with non-coronary forms of atherosclerosis and we need to wait for further contributions with larger number of patients, even if available data seem to suggest an association between small, dense LDL and such diseases. The predominance of small dense LDL particles has been accepted as an emerging cardiovascular risk factor by the National Cholesterol Education Program Adult Treatment Panel III but screening for the presence of small, dense LDL particles in patients with non-coronary forms of atherosclerosis has not been so far recommended.     

Lipid triad or atherogenic lipoprotein phenotype: a role in cardiovascular prevention?

The term "lipid triad" or "atherogenic lipoprotein phenotype" has been introduced to describe a common form of dyslipidemia, characterized by three lipid abnormalities: increased plasma triglyceride levels, decreased HDL-cholesterol concentrations and the presence of small, dense LDL particles. It has been suggested that the clinical importance of the atherogenic lipoprotein phenotype probably exceeds that of LDL-cholesterol, because many more patients with coronary artery disease are found to have this trait than hypercholesterolaemia. There is a body of evidence that therapies effective against plasma HDL-cholesterol and triglycerides are associated with a strong reduction of cardiovascular risk; in addition, hypolipidemic treatment is able to increase LDL particle size and this increment correlates with regression of coronary stenosis. Recently, the Coordinating Committee of the National Cholesterol Education Program suggested that very high-risk patients may benefit from stronger lipid-lowering measures, a category of individuals that includes those with the atherogenic lipoprotein phenotype. Since the therapeutical modulation of each of the three components of the lipid triad is associated with a strong reduction in the risk of cardiovascular events, LDL size measurement may be extended as much as possible to patients at high risk of cardiovascular diseases.     

Low-density lipoprotein particle size, central obesity, cardiovascular fitness, and insulin resistance syndrome markers in obese youths

OBJECTIVE: (1) To determine the prevalence of small dense low-density lipoprotein (SDLDL) particles in obese youths and (2) to compare youths with SDLDL and large buoyant LDL (LBLDL) subclass phenotypes in total body and abdominal fatness, cardiovascular (CV) fitness, and markers of the insulin resistance syndrome (IRS). DESIGN: For group comparisons, subjects were dichotomized into either SDLDL phenotype group or LBDL phenotype group based on LDL particle size. SUBJECTS: Obese 13 to 16-y-olds (n=80) who had a triceps skinfold greater than the 85th percentile for gender, ethnicity, and age. MEASUREMENTS: LDL particle size, plasma lipids and lipoprotein concentrations, plasma glucose and insulin concentrations, and blood pressures; percentage body fat, visceral adipose tissue (VAT); VO(2) at a heart rate of 170 bpm as an index of CV fitness. RESULTS: The prevalence of the SDLDL phenotype was 54% among the 80 obese youths. Although overall body fatness (ie BMI and percentage body fat) and CV fitness were similar between the two LDL phenotype groups, the SDLDL phenotype group had significantly higher weight, waist circumference and VAT than the LBLDL phenotype group. With respect to the IRS markers, youths with the SDLDL phenotype had significantly higher triacylglycerol (TAG), very low-density lipoprotein cholesterol (VLDLC), apolipoprotein B (apo B), and total cholesterol-to-high-density lipoprotein ratio (TC/HDLC) than youths with the LBLDL phenotype. LDL particle size as a continuous variable was significantly correlated with TAG, VLDLC, apo B, HDLC, and TC/HDLC. Plasma TAG and HDLC concentrations were independent predictors of LDL particle size. CONCLUSION: (1) The SDLDL phenotype was common in obese youths and (2) the relationships of LDL particle size with several of the IRS markers suggested that already in adolescence the expression of the SDLDL phenotype might be an important risk factor for future coronary heart disease mortality and morbidity.     

Low-density lipoprotein size and cardiovascular prevention

Low-density lipoprotein (LDL) size appears to be an important predictor of cardiovascular events and progression of coronary artery disease, and the predominance of small, dense LDL has been accepted as an emerging cardiovascular risk factor by the National Cholesterol Education Program Adult Treatment Panel III. Yet, other authors have suggested that LDL subclass measurement does not add independent information to that conferred generically by LDL concentration and other standard risk factors. Therefore, the debate continues as to whether to measure LDL particle size for cardiovascular prevention and, if so, in which categories of patients. Since the therapeutic modulation of distinct LDL subspecies is of great benefit in reducing the risk of cardiovascular events, LDL size measurement should be extended as much as possible to patients at high risk of cardiovascular diseases.     

Effects of diet on genetic regulation of lipoprotein metabolism in baboons

Several measures of lipoprotein phenotype are significant predictors of cardiovascular risk. Although such lipoprotein phenotypes are under strong genetic control, it is not clear to what extent they are controlled by the same - and by different - genes and whether these relationships may be altered in different dietary environments. Therefore, we measured six lipoprotein traits (three LDL traits - LDLC and apoB concentrations and LDL size - and three HDL traits - HDLC and apoA1 concentrations and HDL size) on each of three diets differing in level of fat and cholesterol. In bivariate analyses, all but two metabolically related trait pairs were genetically correlated, though none were completely correlated, implying additive genetic effects by both pleiotropic and unique genes. In comparing genetic correlations for the same pair of traits across diet, we detected evidence of diet effects on genetic control of these metabolically related traits; specifically, increasing level of dietary cholesterol was associated with a significant decrease in the genetic correlation of apoA1 with HDL size, and a significant increase in the genetic correlations of LDL size with LDLC and apoB. The results suggest a complex network of genes affecting lipoprotein metabolism: the genes may exert both unique and pleiotropic effects; the genes may exert detectable effects in many or only in specific dietary environments.     

LDL size in African Americans, Hispanics, and non-Hispanic whites : the insulin resistance atherosclerosis study.

The prevalence of cardiovascular disease (CVD) and atherosclerosis varies among several minority ethnic groups in the United States. Recently, small, dense low density lipoprotein (LDL) particle size has been recognized as a risk factor for CVD. We examined LDL size as a possible explanation for differences in CVD rates in 1571 subjects from the Insulin Resistance Atherosclerosis Study (IRAS), a multiethnic study of insulin resistance and cardiovascular risk factors. LDL size (A) was significantly different by ethnic group (African Americans 262.1+/-0.6, Hispanics 257.6+/-0.6, and non-Hispanic whites 259.2+/-0.4, P<0.001). Ethnic differences in LDL size continued to be statistically significant after adjustment for upper body adiposity, insulin resistance, and glucose tolerance status. However, after further adjustment for other cardiovascular risk factors, especially ethnic differences in triglyceride and high density lipoprotein (HDL) cholesterol levels, the ethnic differences in LDL size were markedly attenuated and in general no longer statistically significant. The relation of triglyceride, HDL cholesterol, insulin resistance, and adiposity to LDL size in each ethnic group was similar. LDL size differs by ethnic group, which is independent of obesity or insulin resistance. These ethnic differences appear to be due to ethnic variations in dyslipidemia (especially differences in triglyceride levels); ethnic differences in LDL size are not consistent with previously reported ethnic dissimilarities in CVD or atherosclerosis.     

The small, dense LDL phenotype and the risk of coronary heart disease: epidemiology, patho-physiology and therapeutic aspects.

More than decade ago, several cross-sectional studies have reported differences in LDL particle size, density and composition between coronary heart disease (CHD) patients and healthy controls. Three recent prospective, nested case-control studies have since confirmed that the presence of small, dense LDL particles was associated with more than a three-fold increase in the risk of CHD. The small, dense LDL phenotype rarely occurs as an isolated disorder. It is most frequently accompanied by hypertriglyceridemia, reduced HDL cholesterol levels, abdominal obesity, insulin resistance and by a series of other metabolic alterations predictive of an impaired endothelial function and increased susceptibility to thrombosis. Whether or not the small, dense LDL phenotype should be considered an independent CHD risk factor remains to be clearly established. The cluster of metabolic abnormalities associated with small, dense LDL particles has been referred to as the insulin resistance-dyslipidemic phenotype of abdominal obesity. Results from the Québec Cardiovascular Study have indicated that individuals displaying three of the numerous features of insulin resistance (elevated plasma insulin and apolipoprotein B concentrations and small, dense LDL particles) showed a remarkable increase in CHD risk. Our data suggest that the increased risk of CHD associated with having small, dense LDL particles may be modulated to a significant extent by the presence/absence of insulin resistance, abdominal obesity and increased LDL particle concentration. We suggest that the complex interactions among the metabolic alterations of the insulin resistance syndrome should be considered when evaluating the risk of CHD associated with the small, dense LDL phenotype. From a therapeutic standpoint, the treatment of this condition should not only aim at reducing plasma triglyceride levels, but also at improving all features of the insulin resistance syndrome, for which body weight loss and mobilization of abdominal fat appear as key elements. Finally, interventions leading to reduction in fasting triglyceride levels will increase LDL particle size and contribute to reduce CHD risk, particularly if plasma apolipoprotein B concentration (as a surrogate of the number of atherogenic particles) is also reduced.     

The low-carbohydrate diet and cardiovascular risk factors: Evidence from epidemiologic studies

AimsObesity is an important public health issue because of its high prevalence and concomitant increase in risk of cardiovascular diseases. Low carbohydrate diets are popular for weight loss and weight management but are not recommended in leading guidelines due to the perception that increases in dietary fat intake may lead to an adverse cardiovascular risk profile. To clarify the effects of a low-carbohydrate diet for weight loss on cardiovascular disease risk factors as compared to a low fat diet for weight loss, we systematically reviewed data from randomized controlled clinical trials and large observational studies.Data synthesisWe searched the MEDLINE database (Jan 1966–Nov 2013) to identify studies that examined a low-carbohydrate diet as compared to a low-fat diet for weight loss or the improvement of cardiovascular disease risk factors.ConclusionsRecent randomized controlled trials document that low-carbohydrate diets not only decrease body weight but also improve cardiovascular risk factors. In light of this evidence from randomized controlled trials, dietary guidelines should be re-visited advocating a healthy low carbohydrate dietary pattern as an alternative dietary strategy for the prevention of obesity and cardiovascular disease risk factors.     

Triglyceride, small, dense low-density lipoprotein, and the atherogenic lipoprotein phenotype

This review provides an overview of the recent data evaluating triglyceride and low-density lipoprotein (LDL) size, two highly interrelated, genetically influenced, risk factors for cardiovascular disease (CVD). An examination of new epidemiologic studies continues to demonstrate that plasma triglyceride levels predict CVD. The first prospective study of the familial forms of hypertriglyceridemia has shown that relatives in familial-combined hyperlipidemia families are at increased risk for CVD mortality and that triglyceride levels predicted 20-year, CVD mortality among relatives in familial hypertriglyceridemia families. A meta-analysis of three, large-scale, prospective studies in men, and the first study to examine the correlation of LDL particle size distribution and vascular changes measured by B-mode ultrasound, add to growing evidence that small, dense LDL is atherogenic. Quantitative genetic analysis has recently shown substantial pleiotropic (common) genetic effects on triglyceride and LDL size. At least part of this may be explained by variation at the cholesterol ester transfer protein locus on chromosome 16, possibly through its role in reverse cholesterol transport. Taken together, these data provide new insights into the importance of triglyceride and LDL particle size for understanding genetic susceptibility to cardiovascular disease and its prevention.     

Influence of dietary carbohydrate and fat on LDL and HDL particle distributions

Variations in the size and density distributions of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles have been related to risk for cardiovascular disease. In particular, increased levels of small, dense LDL particles, together with reduced levels of large HDL and increases in small HDL, are integral features of the atherogenic dyslipidemia found in patients with insulin resistance, obesity, and metabolic syndrome. Increased dietary carbohydrates, particularly simple sugars and starches with high glycemic index, can increase levels of small, dense LDL and HDL, primarily by mechanisms that involve increasing plasma triglyceride concentrations. Low-carbohydrate diets may have the opposite effects. Diets with differing fatty acid composition can also influence LDL and HDL particle distributions.     

The Clinical Relevance of Low-Density-Lipoproteins Size Modulation by Statins

The predominance of small, dense low density lipoproteins (LDL) has been accepted as an emerging cardiovascular risk factor by the National Cholesterol Education Program Adult Treatment Panel III; in fact, LDL size seems to be an important predictor of cardiovascular events and progression of coronary heart disease. Several studies have also shown that the therapeutical modulation of LDL size is of great benefit in reducing the risk of cardiovascular events. Hypolipidemic treatment is able to alter LDL subclass distribution and statins are currently the most widely used lipid-lowering agents. Statins are potent inhibitors of hydroxy-methyl-glutaryl-coenzyme A reductase, the rate-limiting enzyme in hepatic cholesterol synthesis and are the main drugs of choice for the treatment of elevated plasma LDL cholesterol concentrations. Statins potentially lower all LDL subclasses (e.g., large, medium and small particles); thus, their net effect on LDL subclasses or size is often only moderate. However, a strong variation has been noticed among the different agents: analyses of all published studies suggest a very limited role of pravastatin and simvastatin in modifying LDL size and their subclasses, while fluvastatin and atorvastatin seem to be much more effective agents. Finally, rosuvastatin, the latest statin molecule introduced in the market, seems to be promising in altering LDL subclasses towards less atherogenic particles.     

Hypothyroidism results in small dense LDL independent of IRS traits and hypertriglyceridemia

There is evidence of an association between hypothyroidism and coronary heart disease. We decided to look at the relationship between hypothyroidism and LDL subclasses' pattern including small, dense LDL to define a biochemical basis for better management of the CHD risk of these patients. We utilized a case-control design to evaluate differences in lipid parameters between cases and controls. Univariate analysis revealed that many factors were associated with LDL particle size. Binary logistic regression however revealed that only thyroid status and serum triglyceride (TG) levels were independently associated with LDL particle size. Results from this study support an independent association between LDL particle size phenotype and both plasma TG concentrations and thyroid status. After adjusting for TG levels, other insulin resistance syndrome (IRS) traits were not associated with LDL size phenotype, suggesting that the IRS related sdLDL is linked most strongly to alterations in TG levels.     

Smaller LDL particle size in women with polycystic ovary syndrome compared to controls

OBJECTIVE: Women with polycystic ovary syndrome (PCOS) have an increased risk of cardiovascular disease. The contribution of lipid abnormalities to this higher risk, in particular atherogenic modifications of low density lipoprotein (LDL) such as a shift towards smaller LDL, has not been properly explored. We aimed to examine LDL size variation in relation to androgens and other risk factors in women with PCOS. DESIGN: Comparison of clinical and biochemical measurements in women with PCOS and women with normal ovarian function, of similar age and body mass index (BMI). PATIENTS: Thirty-one women with PCOS and 27 controls were studied. Patients were recruited from the outpatient endocrine clinic. MEASUREMENTS: Fasting total cholesterol, triglycerides (TG), high density lipoprotein (HDL), LDL, glucose, insulin, gonadotrophins, androgens, oestradiol, 17 OH progesterone and SHBG were measured. LDL particle diameter was calculated based on distance travelled in polyacrylamide native gels. Recumbent blood pressure was measured automatically. RESULTS: LDL particle size appeared to be significantly smaller in hyperandrogenic PCOS as compared to regularly cycling women (P = 0006), independent of variations in lipid levels. SHBG was the only independent predictor of LDL size in this population, with a strong correlation, which persisted after adjustment for all confounding variables. CONCLUSIONS: Our results suggest that androgen excess and mild insulin-resistance (both responsible for lower SHBG) may have an early modifying effect on low density lipoprotein size in polycystic ovary syndrome women. The denser pattern observed in polycystic ovary syndrome women could by itself constitute a higher cardiovascular risk, even in the absence of overt dyslipidaemia, and contribute to the excess risk of cardiovascular disease reported in this syndrome.     

Relationship of low-density lipoprotein (LDL) particle size to thyroid function status in Koreans

Objective  Dyslipidaemia is a well-known manifestation of thyroid dysfunction. Recently, small low-density lipoprotein (LDL) particle size has been linked with development of cardiovascular disease. To better understand the effects of thyroid dysfunction on the development of cardiovascular disease, we examined LDL particle size and lipid profiles in subjects with different thyroid function.
Methods  Included were 46 patients with overt hypothyroidism, 57 patients with subclinical hypothyroidism, 46 patients with overt hyperthyroidism, 51 patients with subclinical hyperthyroidism, and 110 age- and sex-matched healthy control subjects. We measured LDL particle size and lipid profiles in these subjects.
Results  No significant differences were found in LDL particle size between the groups with different thyroid function. Serum total cholesterol and LDL-cholesterol levels were significantly higher in the cases of hypothyroidism than in the cases of hyperthyroidism and the healthy control subjects. Serum triglyceride levels were higher in subjects with overt hypothyroidism than in those with overt hyperthyroidism or healthy control subjects.
Conclusions  LDL particle size, the emerging risk factor for atherosclerosis, did not appear to be significantly affected by the degree of thyroid dysfunction. Increased risk of atherosclerosis in hypothyroidism does not appear to be associated with LDL particle size, the non-traditional cardiovascular risk factor.     

Hypercholesterinämie – Wo stehen wir heute? Wo wollen wir hin?

Hypercholesterolemia is one of the major modifiable risk factors for the development of atherosclerosis. Increasing LDL cholesterol is associated with an increased risk of developing cardiovascular diseases as well as cardiovascular ischemic complications. Studies with statins and ultimately with ezetimibe have been able to impressively demonstrate that lowering LDL cholesterol contributes to a significant reduction of cardiovascular ischemic complications.Based on the results of randomized trials for lipid lowering, the practice guidelines developed by the professional societies have defined LDL cholesterol goals. High-risk patients, such as patients with clinically manifest cardiovascular disease, type 2 diabetes, type 1 diabetes with organ damage, moderate or severe chronic kidney disease or a risk of SCORE ≥10?%, should reach LDL cholesterol values <70 mg/dl. Data from observational trials demonstrated that in daily practice only about 20?% of treated high-risk patients reached this recommended LDL cholesterol goal. The therapeutic options are not yet exhausted; patients are treated mainly with low or at most average statin dosages. There should be more potent and high-dose statins used as well as the combination therapy of statin and ezetimibe to achieve the recommended LDL cholesterol goals. Specific cardiac rehabilitation and prevention programs with regular benchmarking could support improved goal-achievement. The new therapeutic option of PCSK9 inhibitors, which significantly and safely lower LDL cholesterol on top of statins and ezetimibe, is currently investigated in large randomized outcome trials.     

Acarbose ameliorates atherogenecity of low-density lipoprotein in patients with impaired glucose tolerance

Acarbose, an alpha-glucosidase inhibitor, is administered to control blood glucose levels. The drug also reduces the risk of cardiovascular disease, but the underlying mechanism is still to be elucidated. We therefore hypothesized that treatment with acarbose ameliorates the atherogenecity of low-density lipoprotein (LDL), a key molecule in atherogenesis. Patients with impaired glucose tolerance were or were not treated with acarbose (acarbose-treated group [n = 20] and control group [n = 20], respectively) for 3 months under dietary therapy. The oxidative susceptibility of LDL was determined by measuring lag time for the formation of dienes in the presence of CuSO(4). The lag time was significantly longer in the acarbose-treated group than in the control group before treatment. Moreover, the density gradient lipoprotein separation and disk polyacrylamide gel electrophoresis analyses showed that acarbose reduced the amount of small dense LDL, a more atherogenic and oxidatively susceptible form of LDL. We also found that the fatty acid composition of LDL changed after the treatment: polyunsaturated (omega-3) fatty acid, a beneficial substance for preventing cardiovascular disease, was significantly increased, whereas saturated fatty acids and triglyceride were decreased in the LDL of the acarbose-treated group. The present findings suggest that acarbose treatment reduces the risk of cardiovascular diseases by ameliorating the atherogenecity of LDL.